1-adamantyl and 1-adamantylmethyl carbonates of testosterone and selected derivatives



United States Patent 3,433,813 l-ADAMANTYL AND l-ADAMANTYLMETHYL CARBONATES OF TESTOSTERONE AND SE- LECTED DERIVATIVES George A. Boswell, Green Acres, Wilmington, Del., assignor to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Filed Nov. 29, 1966, Ser. No. 597,555 US. Cl. 260-397.4 12 Claims Int. Cl. C07c 169/24; A61k 17/06 ABSTRACT OF THE DISCLOSURE l-adamantyl or l-adamantylmethyl carbonates of testostosterone or related derivatives represented by the formula:

where R and R are each hydrogen or methyl; n is 0 or 1; and a is a single or double bond; useful as pharmaceuticals.

Fluoroformates of testosterone or related derivatives represented by the formula:

BACKGROUND OF THE INVENTION Field of the invention This invention relates to new esters of testosterone and certain other 17B-hydroxy steroids having the testosterone structures. These esters are the l-adamantyl o1; l-adamantylmethyl carbonates of testosterone or related derivatives, i.e., they are characterized by the presence at the 17-carbon atom of the carbonyldioxy group which is itself attached to a l-adamantyl or l-adamantylmethyl radical.

Description of the prior art Prior art known to the inventor that may be pertinent to the background of the invention is listed as follows:

U.S.P. 3,056,727 to Allais et al., issued Oct. 2, 1962 discloses the cyclohexylcarbonates of testosterone and 3,433,813 Patented Mar. 18, 1969 19-nortestosterone. The cyclohexylcarbonate of testosterone has intense and prolonged androgenic activity.

French Patent 1,215 issued Apr. 2, 1962 to Roussel-- UCLAF discloses testosterone cyclohexylmethyl carbonate (called testosterone hexahydrobenzyl carbonate in the patent) and its preparation from testosterone and cyclohexylmethyl chloroformate. The compound has intense and prolonged androgenic activity, as well as substantial anabolic activity.

French Patent 2,444 issued May 4, 1964 to Rousse1-- UCLAF discloses 19-nortestosterone cyclohexylmethyl carbonate (called 3-oxo-17B-hydroxy A -estrene hexahydrobenzyl carbonate in the patent) and its preparation from 19-nortestosterone and cyclohexylmethyl chloroformate. The product possesses anabolic and androgenic activity.

U.S.P. 3,261,852 issued July 19, 1966 to Rapala discloses the l-adamantoate esters of testosterone and 19- nortestosterone, which are said to be anabolic agents.

SUMMARY OF THE INVENTION The new esters of this invention are represented by the general formula:

where R and R are each hydrogen or methyl; a is a single or double bond between the 4 and 5 carbon atoms of the steroid and when it is a single bond, the S-hydrogen atom is in the a configuration; and n is zero or one.

The invention also includes as new products the fluoroformates of testosterone or related derivatives, which are the intermediates in one of the methods used to prepare the carbonates of the invention. These fluoroformates have the formula:

where R, R and a are defined as above.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 3 4 Ad stands for the l-adamantyl radical and the other where all symbols are the same as in Equation 1. The symbols are those previously defined: process is conducted at a temperature in the range of -CO-F O-CO-O-CHz-Ad Ad-CHaOH HF The process referred to in Equation 1 is carried out at 050 C., preferably 530 C., and in an inert solvent a temperature in the range of 50150 C., preferably 75- which may be any of those mentioned above. The re- 125 C., in an inert solvent such as an aromatic hydroactant proportions are not critical but, as in the case of carbon (e.g., benzene, toluene, xylene) or a halohydroreaction of Equation 1, it is preferred to use at least one carbon (e.g., methylene chloride, carbon tetrachloride, di- 5 mole of l-adamantyl chloroformate per mole of testoschlorotetrafluoroethane, chlorobenzene). The reactant terone and preferably an excess, e.g., up to a molar ratio proportions are not critical, but it is preferred to use at of :1. The reaction is carried out in the presence of a least one mole of l-adamantanemethanol per mole of tertiary amine, used in at least equirnolar amount relative testosterone fiuoroformate, and an exces of the first reto the testosterone and preferably in excess. Alternatively, actant, e.g., up to 20 moles per mole, is advantageously 20 and even preferably, the tertiary amine also serves as at used. The reaction is performed in the presence of a terleast part of the solvent and reaction medium. The tertiary tiary amine which serves as a promoter and also absorbs amines mentioned in connection with reaction of Equathe hydrogen fluoride formed. Suitable acid acceptors are, tion 1 are suitable in this process also. The process condifor example, triethylamine, methyldicyclohexylamine, tritions are similar to those used in the reaction of Equan-hexylamine, pyridine, u-picoline, N-methylpiperidine, tion 1, quiholihe, and the like- The acid acceptor is uSed in at The following examples illustrate the invention in least equirnolar amount relative to the fluoroformate, and greater detail, but are not to b considered limiting, preferably in excess thereover. Moisture is preferably excluded by the use of anhydrous ingredients and by carry- EXAMPLE 1 ing the process out under an inert atmosphere. Pressure and time are not critical. The products are isolated by 17fi-hydroxy-4-estrene-3-one fluoroformate (or: conventional techniques. l9-nortestosterone fiuoroformate) The testosterone fluoroformates are themselves prepared by reacting the testosterone with carbonyl fluoride A solution of 19-nortestosterone (25.0 g-) in methylene in accordance with the equation: chloride (100 ml.) was shaken with carbonyl fluoride at a temperature in the range of 050 C., preferably (75 g.) in a pressure vessel at 20:2 C. for 10 hours. 1540" C., 1n atn inert goltyent uch asftosetn1cn1 1 lel The reaction vessel was then vented, swept out with nitroa ove 1n connec 1on wit t e reaction 0 qua lOIl e t carbonyl fluoride 1s desirably used in molar excess with and Its contents were transferred to Separa my respect to the testosterone for example in a molar ratio funnel. The methylene chloride solution was washed with between 2:1 and 20:1, Th reaction conditions r i water, then with a saturated salt solution, dried over angeheral, the Same as for the reaction of Equation hydrous magnesium sulfate and evaporated to dryness un- The esters of Formula I where n is zero, i.e., the 1- der reduced pressure. The residual clear viscous syrup adamantyl carbonates, can be prepared by the method just described but better results are Obtained by an sol1d1fied on trlturation with hexane. The crude product ternative procedure, which consists in reacting the testos- Was recrystallized from hexane to afford l y Y- terone with l-adamantyl chloroformate in accordance estrene-3-one fluoroformate (23.4 g.) as crystals melting i the equation: at 83-83.5 c., [a] 'I34 (c. 1.47, CHCl 0H AnaIysis,--Calcd. for C H FO C, 71.3; H, 7.85; F,

f\|ij 5.92. Found: C, 71.42; H, 7.84; F, 5.88. Infrared:

l the R i 5.50 (-COF), 6.02 (C-3 conj. C 0), 6.20 (conj. (:C) Ad-O-CO and 3.0 (OCOF). Ultraviolet: 0: 31 60 hi -2.

O-O O-O-Ad l 240 (e=18,000) and 312 mu (e=79). p +HF The fluoroformates of 17f3-hydroxyestrane-3-one, 175- R i hydroxy 70c methylestrane-3-one and 17,8-hydroxy-7amethyl-4-estrene-3-one can be prepared in the same manner, starting with dihydro-l9-nortestosterone, 70t-I1'l6thYldihydro-19-nortestosterone and 7a-methyl-19-nortestosterone, respectively,

EXAMPLE 2 17fi-hydroxy-4-androstene-3-one fluoroformate (or: testosterone fluoroformate) EtOH 17,8-hydroxy-4-estrene 3 one 1' adamantylmethyl carbonate (or: 19 nortestosterone 1' adamantylmethyl carbonate) A solution of 19-nortestosterone fiuoroformate (1.0 g.) and l-adamantanemethanol (10.0 g.) in dry benzene (75 ml.) containing dry pyridine (0.5 ml.) was heated at reflux under nitrogen for 24 hours, during which time a solid (pyridine hydrofluoride) formed in the reflux condenser. The reaction mixture was transferred to a separatory funnel and agitated vigorously with 250 ml. of water. The aqueous phase was drawn off and the remaining organic phase was washed with water, then with saturated salt soltuion, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residual waxy solid was dissolved in hexane and the solution adsorbed onto a column of magnesium silicate chromatographic absorbent. Elution with hexane, followed by crystallization of the solid product thus obtained from hexane, afforded 6.8 g. of recovered l-adamantanemethanol as long colorless needless. Continued elution with hexane containing of acetone brought ofi? a colorless oil which crystallized when triturated with hexane. The crystalline cuts were combined and recrystallized from a mixture of hexane and petroleum ether (B.P. 30-60 C.) to give, as the first crop, 0.646 g. of 17j3-hydroxy-4-es1trene-3-one 1'-adamantylmethyl carbonate. An analytical sample recrystallized from petroleum ether melted at 142.5-143.5 C., [a] +42 (c. 1.65, CHC1 Anal.--Calcd. for C H O C, 77.2; H, 9.07. Found: C, 77.25; H, 8.91. Infrared:

max.

max.

239 (17,200) and 310 Mpt (#78).

The proton n-m-r spectrum supported the assigned structure.

The l-adamantanemethanol used in this example may be prepared as described by Stetter et al. in Ber. 92, 1629 (1959).

Using the same procedure, 17fl-hydroxyestrane-3-one 1-adamantylmethyl carbonate can be prepared from 1713- hydroxy-estrane-3-one fluoroformate; 17/8-hydroxy-7amethylestrane-3-one 1'-adamantylmethyl carbonate from 17 8-hydroxy-h-methyl-estrane-3-0ne fluoroformate; and 17B hydroxy 7a methyl-4-estrene-3-one 1-adamantylmethyl carbonate from 17B-hydroxy-7a-methyl-4-estrene- 3-one fluoroformate.

EXAMPLE 4 17,6 hydroxy '4 androstene 3 one 1' adamantylmethyl carbonate (or: testosterone l'-adamantylmethyl carbonate) A solution of testosterone fluoroformate (2.0 g.) and l-adamantanemethanol (5.62 g.) in dry benzene ml.) containing dry pyridine (0.5 ml.) was heated at reflux under nitrogen for 30 hours, during which time a sublimate of pyridine hydrofluoride formed in the reflux condenser. The reaction mixture was processed as described in Example 3. The infrared spectrum of the crude product showed that a good conversion of the fluoroformate to the carbonate had been achieved.

The crude product was adsorbed from hexane onto a magnesium silicate chromatographic absorbent. Elution with hexane alforded 3.1 g. of recovered l-adamantanemethanol. Continued elution with hexane containing 5% of acetone and recrystallization of the eluted solid from hexane gave colorless crystals (1.5 g.) of hydroxy- 4-androstene-3-one 1-adamantylmethyl carbonate, M.P. 158159 C., [0c] +79 (c. 1.32, CHCl Anal.Calcd. for C H O C, 77.5; H, 9.23. Found: C, 77.47; H, 9.17. Infrared:

5.75 (OCOO), 5.99 (conj. C-3 C=O), 6.18 (conj. C=C) and 8.0 p.

Utraviolet:

EtOH EXAMPLE 5 17fl-hyd-roxy-4-estrene-3-one l'-adamantyl carbonate (or: l9-nortestosterone 1'adamantyl carbonate) This carbonate was prepared by a reaction of 19- nortestosterone with l-adamantyl chloroformate. The latter (M.P. 52-53 C.) was prepared from l-adamantol and phosgene as described by Haas et al. in I. Am. Chem. Soc. 88, 1988 (1966).

To a stirred solution of l9-nortestosterone (6.0 g.) in anhydrous pyridine (35 ml.) cooled to 10 C. was added dropwise a solution in dry benzene (75 ml.) of the l-adamantyl chloroformate obtained from 3.8 g. of l-adamantol. After the addition was completed, the mixture was allowed to warm to room temperature and to stand overnight. During this time a copious amount of pyridine hydrochloride precipitated. The reaction mixture was then processed essentially as described in Example 3 to give a syrupy product, the infrared spectrum of which showed that good conversion to the carbonate had been achieved. This crude product was adsorbed from a small volume of benzene onto a magnesium silicate chromatographic absorbant 150 g.). Elution with hexane containing of acetone gave 0.4 g. of l-adamantol. Further elution with hexane containing 7.5% of acetone returned first the crystalline carbonate, then a mixture of carbonate and unreacted 19-nortestosterone. The carbonate fractions were crystallized from acetone hexane to give 3.47 g. of 17,8-hydroxy-4-estrene-3-one 1'-adamantyl carbonate, M.P. 166-168" C. An analytical sample was recrystallized from the same solvent pair to furnish the product as colorless blades, M.P. 167 C., [a] +35 (c. 1.43, CHCl Anal.--Calcd. for C H O C, 76.9; H, 8.91. Found: C, 77.13; H, 8.98. Infrared:

5.78 (-OCOO), 6.01 (conj. C-3 0 0), 6.20 (conj. @C) and 8.0,u

(CO()OC) 0 Ultraviolet:

Et0H 238 (e=l8,400) and 312 m (6 75).

Using the same procedure, other esters of this invention can be obtained by reaction of l-adamantyl chloroformate with the appropriate testosterone. Thus, 17,6- hydroxyestrane-3-one 1-adamantyl carbonate is obtained from 19-nordihydrostestosterone; 17/8-hydroxy-7a-methylestrane-3-one 1-adamantyl carbonate from 7a-methyl-19- nordihydrotestosterone; 17fl-hydroxy-7a-methyl-4-estrene- 3-one 1'-adamantyl carbonate from 7a-methyl-19-nortestosterone; 17B-hydroxy 4 androstene-3-0ne l-adamantyl carbonate from testosterone; l7fi-hydroxyandrostane-3-one 1-adamantylcarbonate from dihydrotestosterone; l7fl-hydroxy-7a-methylandrostane-3-one 1'-adamantyl carbonate from 7a-methyldihydrotestosterone; and 17 3 hydroxy-7a-methyl-4-androstene-3-one 1-adamantyl carbonate from 7a-methyltestosterone.

The products of this invention possess marked pharmacological activity. The l-adamantyl and l-adamantylmethyl carbonates of testosterone and related derivatives have an androgenic-anabolic action and they can be used in place of testosterone and its simple esters in instances where such an action is desired. Since these compounds are very soluble in oil bases and have a prolonged duration of action due to the slow hydrolysis of the bulky carbonate to release the active species, a single massive dose is still eifective many weeks after injection, thus behaving in the manner of a true implant. The l-adamantyl and l-adamantylmethyl carbonates of 19-n0rtestosterone and related derivatives are anabolic-androgenic agents with a favorable anabolic to androgenic ratio and are emiently suitable in those instances where an intense and prolonged anabolic effect is needed. For example, these carbonates are useful to promote weight gain, to increase muscular strength, and to promote a sense of well-being in mammals.

The fluoroformates of testosterone, 19-nortestosterone and related derivatives are characterized by having anabolic-androgenic activity in mammals and birds and thus are useful in male gonadal replacement therapy in prepuberal and postpuberal castrates, in pituitary dwarfism, etc. The fiuoroformates are potent inhibitors of pituitary secretion and therefore can be used to regulate estrus in mammals, e.g., in valuable domestic animals. In addition, these compounds have an antifertility effect in mammals and hence are agents for controlling animal populations. 19-n0rtestosterone fluoroformate has a favorable anabolic to androgenic ratio, making it useful to promote growth and weight gain in valuable domestic animals.

-(EMQ wherein R and R are each selected from the class consisting of hydrogen and methyl; a represents a bond between carbon atoms 4 and 5 of the steroid nucleus selected from the class consisting of a single bond and a double bond, and when a is a single bond the S-hydrogen is in the a configuration; and n is a number selected from the class consisting of zero and 1; and

ll 0- C-F wherein R, R and a are defined as above.

2. Compounds of claim 1 represented by the formula wherein R, R a and n are defined as in claim 1.

3. Compounds of claim 1 represented by the formula wherein R, R and a are defined as in claim 1. 4. Compounds of claim 2 wherein n is zero. 5. Compounds of claim 2 wherein n is 1. 6. Compounds of claim 2 wherein R is hydrogen. 7. Compounds of claim 2 wherein R is methyl. 8. The compound of claim 2 represented by the formula 9 10 1'1. The compound of claim 3 represented by the forll mula oc- 0- c'na 0 O-B-F 5 9. The compound of claim 2 represented by the formula 0 O 12. The compound of claim 3 represented by the for- O-C-O-CHZQ ula 10. The compound of claim 2 represented by the formula 0 0 References Cited ll UNITED STATES PATENTS 3,056,727 1-0/1962 Allais et a1.

3,261,852 7/1966 Rapala. H HENRY A. FRENCH, Primary Examiner.

3 us. 01. X.R. o 260999 g 

